BMJ 2014;348:g2301 doi: 10.1136/bmj.

g2301 (Published 15 April 2014) Page 1 of 20

Research

RESEARCH

Chronic hypertension and pregnancy outcomes:

systematic review and meta-analysis
OPEN ACCESS

Kate Bramham clinical research fellow, Bethany Parnell medical student, Catherine Nelson-Piercy
professor of obstetric medicine, Paul T Seed senior lecturer in medical statistics, Lucilla Poston
professor of Women’s Health, Lucy C Chappell clinical senior lecturer in maternal and fetal medicine
Division of Women’s Health, Women’s Health Academic Centre, King’s College London and King’s Health Partners, St Thomas’ Hospital, London
SE1 7EH, United Kingdom

Abstract
Objective To provide an accurate assessment of complications of
pregnancy in women with chronic hypertension, including comparison
with population pregnancy data (US) to inform pre-pregnancy and
antenatal management strategies.
Design Systematic review and meta-analysis.
Data sources Embase, Medline, and Web of Science were searched
without language restrictions, from first publication until June 2013; the
bibliographies of relevant articles and reviews were hand searched for
additional reports.
Study selection Studies involving pregnant women with chronic
hypertension, including retrospective and prospective cohorts, population
studies, and appropriate arms of randomised controlled trials, were
included.
Data extraction Pooled incidence for each pregnancy outcome was
reported and, for US studies, compared with US general population
incidence from the National Vital Statistics Report (2006).
Results 55 eligible studies were identified, encompassing 795 221
pregnancies. Women with chronic hypertension had high pooled
incidences of superimposed pre-eclampsia (25.9%, 95% confidence
interval 21.0% to 31.5 %), caesarean section (41.4%, 35.5% to 47.7%),
preterm delivery <37 weeks’ gestation (28.1% (22.6 to 34.4%), birth
weight <2500 g (16.9%, 13.1% to 21.5%), neonatal unit admission
(20.5%, 15.7% to 26.4%), and perinatal death (4.0%, 2.9% to 5.4%).
However, considerable heterogeneity existed in the reported incidence
2
of all outcomes (τ =0.286-0.766), with a substantial range of incidences
in individual studies around these averages; additional meta-regression
did not identify any influential demographic factors. The incidences (the
meta-analysis average from US studies) of adverse outcomes in women
with chronic hypertension were compared with women from the US
national population dataset and showed higher risks in those with chronic
hypertension: relative risks were 7.7 (95% confidence interval 5.7 to
10.1) for superimposed pre-eclampsia compared with pre-eclampsia,
1.3 (1.1 to 1.5) for caesarean section, 2.7 (1.9 to 3.6) for preterm delivery
<37 weeks’ gestation, 2.7 (1.9 to 3.8) for birth weight <2500 g, 3.2 (2.2
to 4.4) for neonatal unit admission, and 4.2 (2.7 to 6.5) for perinatal
death.
Conclusions This systematic review, reporting meta-analysed data
from studies of pregnant women with chronic hypertension, shows that
adverse outcomes of pregnancy are common and emphasises a need
for heightened antenatal surveillance. A consistent strategy to study
women with chronic hypertension is needed, as previous study designs
have been diverse. These findings should inform counselling and
contribute to optimisation of maternal health, drug treatment, and
pre-pregnancy management in women affected by chronic hypertension.
Introduction
Chronic hypertension complicates between 1% and 5% of
pregnancies,1-4 but this estimate is drawn from a small number
of population based studies, including publications from more
than 20 years ago. Recent demographic changes in the antenatal
population suggest that chronic hypertension in pregnancy may
be an increasing clinical problem. In populations in which
maternal age at childbirth is increasing, the association of
hypertension with advancing age will inevitably contribute to
a greater prevalence of chronic hypertension.5 In the United
States, for example, chronic hypertension is likely to have
paralleled the increase in first deliveries in women aged over
35 years from 1% to 8% that occurred between 1970 and 2006.6
Maternal age may not be the only factor; a recent population
based study in the United States suggests that the prevalence of
chronic hypertension in pregnancy increased between 1995-96
and 2007-08, despite adjustment for maternal age.4 An increase
in other risk factors for chronic hypertension, including obesity
and the metabolic syndrome, is likely to contribute.7 8 Globally,
therefore, the number of women entering pregnancy with
established chronic hypertension is set to rise.9

Correspondence to: L Chappell lucy.chappell@kcl.ac.uk

Extra material supplied by the author (see http://www.bmj.com/content/348/bmj.g2301?tab=related#webextra)

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
Chronic hypertension is associated with poor outcomes of
pregnancy.10 Numerous case-control studies frequently identify
chronic hypertension as a risk factor for most known adverse
events for mother and fetus.11-13 Retrospective and prospective
cohort studies, intervention trials, and observational studies for
high risk pregnancies similarly document higher rates of
complications of pregnancy in women with chronic
hypertension.8 14-16 Individually, these reports, usually from
single centre studies, provide valuable data for a given
population, but they are of limited use for wider extrapolation.
Nevertheless, collectively, they may enable accurate assessment
of pregnancy outcomes in affected women.
Primary and secondary healthcare professionals involved in the
management of women of childbearing age with chronic
hypertension include family doctors, clinical pharmacologists,
cardiologists, nephrologists, endocrinologists, and general
physicians. All may be called on to provide information for
women planning a pregnancy. Pregnancy is frequently the first
time when chronic hypertension is identified by midwives and
obstetricians.17 In the absence of a strong evidence base for
accurate risk assessment in chronic hypertension, providing
useful estimates of adverse pregnancy outcomes presents a
challenge. The objective of this study was to conduct a
meta-analysis of population based, multicentre, and single centre
studies, to provide a reliable assessment of risks of pregnancy
in women with chronic hypertension, drawing comparison with
outcomes available from US studies and the US general
population (2006) of pregnant women.
Methods
Literature review
We did a comprehensive literature review using the databases
PubMed/Medline (via OVID), Embase (via OVID), and Web
of Science. We tailored search strategies to each database. We
used MeSH and free text terms in conjunction to increase
sensitivity to potentially appropriate studies. Where MeSH terms
were not used (Web of Science), we identified search terms and
all possible synonyms and spellings obtained and used them in
the search strategy. In Web of Science, we selected the
“lemmatisation” option. We searched pregnancy complications
and outcomes terms and chronic hypertension terms separately,
and then combined them in each database. The study protocol
is provided in supplementary information 1. We applied no
limits other than the search strategy to databases. We searched
databases from the time of first publication (Medline 1946,
Embase 1947, Web of Science 1899) until June 2013.
Study selection criteria
We included prospective and retrospective cohort studies. We
reviewed randomised controlled trials, excluding the treatment
arm if a difference existed in outcomes and including both arms
if no benefit of the intervention was seen. We excluded
case-control studies, case reports, reviews, letters to editors, and
animal/in vitro studies.
To minimise selection bias, we did not include studies that
excluded women with superimposed pre-eclampsia or
categorised women with chronic hypertension and superimposed
pre-eclampsia together with low risk women with pre-eclampsia,
as this was one of the outcomes of interest. We considered
studies with fewer than 20 women with chronic hypertension
to be non-representative, and we excluded studies that did not
report relevant outcome data.
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 2 of 20
RESEARCH
Data extraction
KB and BP independently reviewed abstracts and full texts, and
LC reviewed any discrepancies. The same authors independently
extracted and tabulated data from selected full texts. When two
studies included the same cohort, we included only the report
with the largest number of women or most relevant outcomes.
We followed PRISMA guidelines for all procedures and
reporting.18 We used the Newcastle-Ottawa scale to grade cohort
studies. We considered multi-fetal gestations as one pregnancy
for maternal outcomes and two pregnancies for fetal outcomes.
We recorded details of other potential confounders and
adjustments, including age, secondary hypertension, body mass
index, weight, parity, smoking, and ethnicity. Manuscripts not
published in English were translated by native speaking
physicians. We included abstracts if a definition of chronic
hypertension and relevant outcomes were described.
We examined and reported definitions of chronic hypertension
and superimposed pre-eclampsia (when available) for each
included study. For purposes of analysis, we used the following
definitions: preterm delivery—delivery before 37 weeks’
gestation (up to 36+6); low birth weight—below 2500 g; perinatal
death—fetal death after 20 weeks’ gestation including stillbirth
and neonatal death up to 1 month; neonatal unit
admission—admission to neonatal intensive care or special care
baby unit.
Statistical analysis
We used mixed effects logistic regression for meta-analysis,
using the Stata command “xtmelogit.” We used extracted data
to calculate estimated pooled incidences, 95% confidence
intervals, and predicted 95% incidence ranges (prediction
intervals) of adverse outcomes. Prediction intervals have been
proposed as being akin to a reference range for that parameter
across the population, allowing more appropriate interpretation
and extrapolation into clinical practice.19 Ninety five per cent
prediction intervals show the uncertainty of the range of possible
percentage incidences for a new study population, whereas 95%
confidence intervals show the uncertainty about the estimate of
the average percentage incidence across study populations.
We used mixed effects logistic regression, which allows for
random variation at more than one level, on the assumption that
significant heterogeneity would exist both between individuals
and between studies and that each study would be likely to
include covariates that could influence outcomes. We used the
τ2 statistic to describe heterogeneity and did subgroup analyses
according to seven groupings selected before analysis: country’s
economic wealth according to World Bank classification (gross
national income per capita),20 study period, inclusion or
exclusion of multiple pregnancies, inclusion or exclusion of
congenital abnormalities, inclusion or exclusion of women with
secondary hypertension, study design, and study definition of
chronic hypertension. We also stratified studies reporting
incidences of superimposed pre-eclampsia according to the
study definition of superimposed pre-eclampsia. We used forest
plots to assess overall effect. We calculated risk ratios for US
studies relative to separate comparator data obtained from the
Centers for Disease Control and Prevention’s vital statistics
2006 (US national statistics) for pooled incidences and for
individual study outcomes.21
We also did meta-regression using “xtmelogit” regression to
identify the influence of potential modifiers of outcome
including parity, maternal age, and ethnicity on the relation
between chronic hypertension and subsequent outcome. As
individual level data were unavailable, we used aggregate data
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
for each study (mean and standard deviation for age, and
proportions of nulliparous/multiparous and white/non-white
women). We made estimates of mean age if categories of ranges
were presented. We used Stata version 11 for all statistical
analyses, and all tests and confidence intervals were two sided
with a significance level of 0.05.
Results
Figure 1⇓ shows the study selection process. Following
title/abstract screening, 208 papers remained for full text review.
Four abstracts were unavailable for analysis despite repeated
attempts to contact the authors. Fifty five studies, comprising
795 221 pregnancies and 812 772 infants, met inclusion criteria
and are reported in tables 1⇓, 2⇓, 3⇓, and 4⇓.15 16 22-74 All studies
achieved a total Newcastle-Ottawa grading score of 5 to 7, and
no studies were excluded following grading. Newcastle-Ottawa
gradings are shown in supplementary information 2.
Five studies were randomised controlled trials, including a
primary analysis,16 three secondary analyses of studies that did
not have differences between treatment and placebo arms,15 22 24
and one study that reported a difference in outcomes between
the treatment (L-arginine supplementation) and placebo arm,23
so only the placebo arm was included. One study included both
prospective and retrospective data and was categorised as
retrospective as this was the larger group.32
Maternal demographics of women with chronic hypertension,
if reported, are shown in online supplementary information 2.
Individual study definitions of chronic hypertension and
categories according to definition are shown in tables 1⇓, 2⇓,
3⇓, and 4⇓ and in more detail in online supplementary
information 3. Study definitions for superimposed pre-eclampsia
are shown in online supplementary information 4. Table 5⇓
shows pooled incidences and prediction intervals of adverse
pregnancy outcomes. Table 6⇓ shows risk ratios of adverse
pregnancy outcomes from US studies compared with US
population data.
The relative risk of superimposed pre-eclampsia in women with
chronic hypertension was on average across study populations
nearly eightfold higher than was pre-eclampsia in the general
pregnancy population, and all adverse neonatal outcomes were
at least twice as likely to occur compared with the general
population.
The meta-analysis summary results and 95% confidence
intervals relate to the average percentage incidence across
studies. However, heterogeneity existed in most analyses, as
seen by τ2 values above zero. Thus genuine variation in
incidences exists across study populations; in other words, in
some populations the true incidence is well above the average,
and in others it is well below the average. This is shown by wide
95% prediction intervals for the potential percentage incidence
in a new study population. Only the limits of the prediction
interval for superimposed pre-eclampsia excluded the US
national data incidence of pre-eclampsia, which shows that the
increased rate was evident across the different settings of the
studies.
Figures 2⇓, 3⇓, 4⇓, 5⇓, 6⇓, and 7⇓ show forest plots for the
pooled incidence of superimposed pre-eclampsia, caesarean
section, preterm delivery before 37 weeks’ gestation, birth
weight <2500 g, perinatal death, and neonatal unit admission.
Heterogeneity of incidence of superimposed pre-eclampsia
seemed to be lower in randomised controlled trials (τ2=0.026)
than in population studies (τ2=0.438) and was greater in
prospective cohort (τ2=0.83) and retrospective cohort studies
(τ2=1.080). Stratification of studies according to study definitions
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 3 of 20
RESEARCH
of superimposed pre-eclampsia did not further reduce
heterogeneity measured by τ2. The incidence of neonatal unit
admission was lower in one population study (7.1%, 95%
confidence interval 6.0% to 9.2%) compared with randomised
controlled trials (20.1%, 19.5% to 24.3%), but only one
population study was included in this subgroup analysis.
Further comparison of τ2 did not identify any significant
influence of multiple pregnancies, congenital abnormalities,
period of delivery, country’s economic wealth, inclusion of
secondary hypertension, maternal age, parity, ethnicity, or study
definition of chronic hypertension on the degree of heterogeneity
(τ2>0.2 for all subgroups) or proportion of women with adverse
events.
Discussion
This meta-analysis of 55 studies from 25 countries, including
795 221 pregnancies and spanning four decades, confirms that
chronic hypertension is associated with adverse pregnancy
outcomes. The pooled average incidence, across study
populations, of superimposed pre-eclampsia, caesarean section,
preterm delivery before 37 weeks’ gestation, birth weight <2500
g, perinatal death, and neonatal unit admission were all
significantly higher in US studies than the general US pregnancy
population. Moreover, for superimposed pre-eclampsia, the
limits of the 95% prediction intervals (reference range) for the
US based studies were higher than the rate of pre-eclampsia
reported in the US population. Heterogeneity between studies
existed, and 95% prediction intervals were broad. Incidences
of superimposed pre-eclampsia reported by randomised
controlled trials were less heterogeneous than for other study
designs but similar to the overall pooled incidence of
superimposed pre-eclampsia in women with chronic
hypertension. However, meta-regression did not identify any
other underlying causes of heterogeneity, suggesting that either
populations with chronic hypertension are varied or
determination of chronic hypertension and outcomes may not
be consistent.
Strengths and weaknesses of study
Studies were carefully selected according to a rigorous search
strategy to enable unbiased inclusion of retrospectively or
prospectively studied cohorts, population studies, or randomised
controlled trials. For example, superimposed pre-eclampsia has
been shown to be associated with worse pregnancy
outcomes,15 75-79 but some reports, initially assessed for the
purpose of this study, excluded women with chronic
hypertension and superimposed pre-eclampsia. This would lead
to an underestimation of other adverse events, so we did not
include these publications in the analysis. In other studies,
women with superimposed pre-eclampsia were frequently
grouped with other women with pre-eclampsia alone, precluding
useful risk assessment for women with chronic hypertension.
These studies were also excluded from meta-analysis.
Despite the selection of relevant and appropriately performed
studies, we observed substantial diversity of reported incidences
of adverse outcome. This is likely to reflect variations in the
selection of women studied and difficulties of measurement but
also true differences within the population of women with
chronic hypertension. We conducted exploration to identify
important confounders, including maternal age, ethnicity,
economic wealth of country, decade of deliveries reported,
parity, inclusion of secondary hypertension, multiple pregnancies
and congenital birth defects, study design, and study definition
of chronic hypertension. Although randomised controlled trials
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
were more consistent than other study designs, we found no
systematic differences in mean event rates to explain the
disparity in outcomes. Most papers did not report relevant
baseline demographics defining the population studied, which
limited the assessment of confounders. Coexisting factors
including maternal age and ethnicity, recognised to be associated
with both chronic hypertension and adverse pregnancy outcome,
may contribute to confounding, but their relative effects are
unknown.
Few studies in the meta-analysis reported control data, so a
direct comparison of outcomes between women with chronic
hypertension and normotensive women was not possible. To
provide clinical context and relevance, we selected US
population data (2006)21 as a separate population for comparison
against the US chronic hypertension studies, because these data
provide the most comprehensive national annual statistics.
Although US population data also report outcomes in high risk
women, including those with chronic hypertension, the
proportion of women with chronic hypertension in this dataset
is small and therefore unlikely to influence the overall incidence
of adverse outcomes. We chose the dataset from 2006 as being
sufficiently recent to be clinically relevant but not too
chronologically distant from the years in which most of the
studies were conducted.
We could not elucidate the effect of differing antihypertensive
treatments on the maternal and perinatal outcomes, as
insufficient information was provided to allow subanalysis by
drug group. This problem is made more complex by scenarios
that include changing treatment over the gestation—for example,
when a pregnant woman starts pregnancy while taking one drug,
stops all treatment during the mid-trimester blood pressure nadir,
and then restarts with a different drug when her blood pressure
exceeds a certain threshold. In addition, many population based
registry studies may record prescriptions from a database, rather
than provide data that confirm that treatment has been taken.
Thus assigning an individual woman to any drug treatment is
difficult even within trimesters.
Strengths and weaknesses in relation to other
studies
To our knowledge, few other detailed meta-analyses of outcomes
of pregnancy in women with chronic hypertension have been
reported. Population studies have reported data from large
numbers of women with chronic hypertension and can be a
useful guide to risks of pregnancy, but their generalisability is
unclear. Population studies are limited by inaccuracies of coding
collected for billing purposes and are susceptible to
under-recognition of hypertension in pregnancy and
misclassification. For example, Roberts and colleagues
compared hospital discharge and birth databases with medical
records and identified significant under-reporting of chronic
hypertension.3 Inadequacies of coding are also particularly
relevant to accurate diagnosis of pre-eclampsia.80 Women are
more likely to be reported to have chronic hypertension if it had
been recorded in an admission before pregnancy,3 suggesting
that women with more severe or longstanding chronic
hypertension may be more likely to be included in population
studies.
No threshold of blood pressure that predicts poor pregnancy
outcomes has been identified, and an association between both
systolic and diastolic blood pressure and adverse events has
been reported.81 Similarly, the length of time between diagnosis
of hypertension and pregnancy is associated with more adverse
events.24 Chronic hypertension may be undetectable in early
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 4 of 20
RESEARCH
pregnancy owing to systemic vasodilatation and reduced
vascular resistance,82 resulting in a fall in blood pressure, so
women with a blood pressure below 140/90 mm Hg before 20
weeks’ gestation would be excluded from many of the studies
assessed, unless they were already taking antihypertensive drugs
during or before pregnancy. The identification of women with
chronic hypertension is therefore challenging, and the fact that
multiple different definitions of chronic hypertension were given
is unsurprising. This may explain some diversity in incidence
of adverse events between studies; however, categorisation of
studies according to definition of chronic hypertension did not
reduce heterogeneity between outcomes.
In keeping with the challenges of diagnosing chronic
hypertension, identification of superimposed pre-eclampsia
remains difficult, and uncertainties exist. Research definitions
have gone some way towards standardising diagnoses.83 In this
meta-analysis, 16 (30%) studies did not report diagnostic criteria,
and the remainder used 18 varying, though valid, definitions of
superimposed pre-eclampsia. Lack of consistency is likely to
affect the heterogeneity of outcomes across studies.
Although women with more severe chronic hypertension,
managed in specialist clinics, may be over-represented in some
cohort studies, pregnancy outcomes did not differ by definition
of inclusion criteria. Lack of blood pressures at first antenatal
visit or use of antihypertensive drugs in early pregnancy
precluded assessment of outcomes by severity of hypertension,
although degree of hypertension clearly affects the decision for
treatment and outcomes may therefore be influenced by severity.
The findings of this study remain applicable to the women with
chronic hypertension most frequently encountered and most in
need of specialist advice.
Meanings of study and implications for
physicians and health providers
The most recent UK Confidential Enquiry into Maternal and
Child Health identified chronic disease as an underlying factor
in preventable maternal deaths.84 Consequently, the first
recommendation stated that “Pre-pregnancy counselling services,
. . . for women with pre-existing medical illnesses . . . are a key
part of maternity services,” supported by the National Institute
for Health and Care Excellence’s guidelines for the management
of hypertension in pregnancy.85 Furthermore, the American
Congress of Obstetricians and Gynecologists’ recent practice
bulletin recommends that women with chronic hypertension
“should be evaluated before conception to ascertain possible
end-organ involvement.”86 Systematic reviews and meta-analyses
can provide data more readily inferable to the individual, but
no large aggregate analysis of pregnancy outcome in women
with chronic hypertension has previously been reported. This
meta-analysis of outcomes can be used before pregnancy and
antenatally by healthcare professionals (including those not
providing direct maternity care) advising women with chronic
hypertension regarding possible adverse pregnancy events.
Accessibility to healthcare professionals and facilitation of early
referral will allow drug treatment to be optimised on an
individual basis (for example, starting aspirin and planning a
change from cardio-renoprotective angiotensin converting
enzyme inhibitors and angiotensin-II receptor blockers to
alternative non-teratogenic antihypertensive drugs at the first
positive pregnancy test or pre-pregnancy) or enable reassurance
regarding continuation of drugs that are safe in pregnancy, to
reduce the risk of complications including cerebrovascular
events.
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
Debate is ongoing as to how antihypertensive treatment
influences outcomes. Although reasonable evidence from a
Cochrane systematic review shows that use of antihypertensive
drugs halves the incidence of severe hypertension, it has not
been shown to affect any other outcomes, including risk of
pre-eclampsia, perinatal death, preterm birth, or small for
gestational age babies.87 Recent work has found that the risk of
certain malformations such as congenital heart disease is similar
in women taking angiotensin converting enzyme inhibitors and
those with underlying hypertension taking no treatment, both
having increased risk compared with normotensive controls,
suggesting that the hypertension itself may contribute to
congenital malformations.88 Systematic reviews have also
identified that a greater mean difference in mean arterial pressure
with antihypertensive treatment is associated with the birth of
a higher proportion of small for gestational age infants,89
providing the basis for the Chronic Hypertension In Pregnancy
Study (CHIPS). This study, which has recently completed
recruitment of more than 1000 women with hypertension in
pregnancy, but is yet to report, was designed to determine
whether tight or less tight blood pressure control influences the
likelihood of pregnancy loss or neonatal intensive care unit
admission.90 A recent study showing that women with chronic
hypertension taking antihypertensive drugs have worse perinatal
outcomes than do those not on treatment was unable to adjust
for severity of underlying hypertension and indicates the need
for future prospective studies to explore the influence of
pre-existing disease severity.91
While the debate on the use and type of antihypertensive drugs
continues, other beneficial management strategies needing
implementation before or in early pregnancy include lifestyle
adjustments (such as weight loss).92 Our group has previously
shown that women with chronic hypertension who continue to
smoke in pregnancy are at greater risk of superimposed
pre-eclampsia (compared with non-smokers), so smoking
cessation is also an essential component of counselling.
Future research
Increasing numbers of pregnancies will be complicated by
chronic hypertension as the trend continues for women to delay
conception, together with the global epidemic of obesity. The
consequences of complicated pregnancy outcome are not only
costly in the short term, but the long term health consequence
for the offspring of women with chronic hypertension and the
subsequent financial burden should be acknowledged.93 The
findings of this meta-analysis support the need for improved
understanding of the pathophysiology of chronic hypertension,
to inform the development of predictive and diagnostic tools
and enhance therapeutic interventions to reduce adverse
pregnancy outcomes. The continuing uncertainty about maternal
and perinatal effects of antihypertensive treatment shows the
need for large observational studies (for example, through
population registers) and randomised controlled trials of drug
treatment in women with chronic hypertension, to determine
optimal management for mother and fetus. As severity of
hypertension will always confound need for treatment and
perinatal outcomes, this must be considered for appropriate
conclusions to be drawn.
Conclusions
Chronic hypertension is associated with a high incidence of
adverse pregnancy outcomes compared with a general
population, as exemplified in this report by US data. This finding
should be interpreted within the limitations of the study. Our
results support the importance of increased antenatal surveillance
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 5 of 20
RESEARCH
for women with chronic hypertension to enable early
identification of evolving complications. Women should receive
pre-pregnancy counselling to optimise their health before
pregnancy and to inform them of the increased maternal and
fetal risks associated with their hypertension. Strategies to
predict those at greatest risk, determine optimal drug treatments,
and reduce adverse pregnancy outcomes are needed.
Contributors: KB, BP, and LCC contributed to study conception and
design, analysis and interpretation of the data, and drafting and revising
of the article and were involved in the final approval of the version to
be published. PTS contributed to the analysis and interpretation of the
data and revision of the article. CN-P and LP contributed to the
interpretation of the data, drafting and revising of the article, and approval
of the final paper. LCC is the guarantor.
Funding: This work is produced by KB under the terms of a doctoral
research training fellowship issued by the National Institute for Health
Research. The views expressed in this publication are those of the
author and not necessarily those of the NHS, the National Institute for
Health Research, or the Department of Health. PTS’s salary is funded
by Tommy’s Charity.
Competing interests: All authors have completed the ICMJE uniform
disclosure form at www.icmje.org/coi_disclosure.pdf (available on
request from the corresponding author) and declare: no support from
any organisation for the submitted work; no financial relationships with
any organisations that might have an interest in the submitted work in
the previous three years; no other relationships or activities that could
have influenced the submitted work.
Ethical approval: Not needed
Transparency declaration: LCC affirms that the manuscript is an honest,
accurate, and transparent account of the study being reported; that no
important aspects of the study have been omitted; and that any
discrepancies from the study as planned (and, if relevant, registered)
have been explained.
Data sharing: The dataset is available to interested academic parties
from the corresponding author.
1 Haddad B, Sibai BM. Chronic hypertension in pregnancy. Ann Med 1999;31:246-52.
2 Livingston JC, Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol Clin North
Am 2001;28:447-63.
3 Roberts CL, Bell JC, Ford JB, Hadfield RM, Algert CS, Morris JM. The accuracy of reporting
of the hypertensive disorders of pregnancy in population health data. Hypertens Pregnancy
2008;27:285-97.
4 Bateman BT, Bansil P, Hernandez-Diaz S, Mhyre JM, Callaghan WM, Kuklina EV.
Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery
5
admissions. Am J Obstet Gynecol 2012;206:134.e1-8.
Yoder SR, Thornburg LL, Bisognano JD. Hypertension in pregnancy and women of
childbearing age. Am J Med 2009;122:890-5.
6 Mathews TJ, Hamilton BE. Delayed childbearing: more women are having their first child
later in life. National Center for Health Statistics Data Brief 2009;21.
7 Bayliss H, Churchill D, Beevers M, Beevers DG. Anti-hypertensive drugs in pregnancy
and fetal growth: evidence for “pharmacological programming” in the first trimester?
Hypertens Pregnancy 2002;21:161-74.
8 Ananth CV, Peedicayil A, Savitz DA. Effect of hypertensive diseases in pregnancy on
birthweight, gestational duration, and small-for-gestational-age births. Epidemiology
9
1995;6:391-5.
Seely EW, Ecker J. Chronic hypertension in pregnancy. N Engl J Med 2011;365:439-46.
10 Chesley LC. Toxemia of pregnancy in relation to chronic hypertension. West J Surg Obstet
11
Gynecol 1956;64:284-6.
Aagaard-Tillery KM, Holmgren C, Lacoursiere DY, Houssain S, Bloebaum L, Satterfield
R, et al. Factors associated with nonanomalous stillbirths: the Utah Stillbirth Database
1992-2002. Am J Obstet Gynecol 2006;194:849-54.
12 Ananth C, Peltier M, Smulian J, Vintzileos A. Chronic hypertension and risk of placental
abruption: is the association mediated through fetal growth? Am J Obstet Gynecol
2007;197:273.e1-7.
13 Berg CJ, MacKay AR, Qin C, Callaghan WM. Overview of maternal morbidity during
hospitalization for labor and delivery in the United States 1993-1997 and 2001-2005.
Obstet Gynecol 2009;113:1075-81.
14 Sibai B, Lecarpentier E, Kayem G, Haddad B, Tsatsaris V, Goffinet F. Adverse maternal
and perinatal outcomes in women with chronic hypertension: a retrospective study of 362
patients. Am J Obstet Gynecol 2011;204:S294.
15 Chappell LC, Enye S, Seed P, Briley AL, Poston L, Shennan AH. Adverse perinatal
outcomes and risk factors for preeclampsia in women with chronic hypertension: a
16
prospective study. Hypertension 2008;51:1002-9.
Weitz C, Khouzami V, Maxwell K, Johnson JW. Treatment of hypertension in pregnancy
with methyldopa: a randomized double blind study. Int J Gynaecol Obstet 1987;25:35-40.
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
What is already known on this topic
Women with chronic hypertension have worse outcomes of pregnancy
The magnitude of pregnancy risk for women with chronic hypertension is uncertain from pre-existing data
What this study adds
This systematic review and meta-analysis shows that women with chronic hypertension have a high pooled incidence of superimposed
pre-eclampsia and all other pregnancy complications
Compared with the US general pregnancy population, the incidence of superimposed pre-eclampsia on average across study populations
was nearly eightfold higher compared with pre-eclampsia
Women with chronic hypertension in US studies have an approximately threefold increased risk of delivery before 37 weeks’ gestation,
birth weight <2500 g, and neonatal intensive care admission and fourfold increased risk of perinatal death compared with the US general
pregnancy population
17 Vallejo Vaz AJ, Guisado ML, Garcia-Junco PS, Andreu EP, Morillo SG, Ortiz JV.
Differences in the prevalence of metabolic syndrome and levels of C-reactive protein after
puerperium in women with hypertensive disorders during pregnancy. Hypertens Res
2010;33:1012-7.
18 Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis
of observational studies in epidemiology: a proposal for reporting. JAMA 2000;283:2008-12.
19 Riley RD, Higgins JP, Deeks JJ. Interpretation of random effects meta-analyses. BMJ
2011;342:d549.
20 World Health Organization. Countries and economies. 2013. http://data.worldbank.org/
country.
21 Center for Disease Control and Prevention. Births and natality. 2006. www.cdc.gov/nchs/
fastats/births.htm.
22 August P, Helseth G, Cook EF, Sison C. A prediction model for superimposed preeclampsia
in women with chronic hypertension during pregnancy. Am J Obstet Gynecol
2004;191:1666-72.
23 Neri I, Monari F, Sgarbi L, Berardi A, Masellis G, Facchinetti F. L-arginine supplementation
in women with chronic hypertension: impact on blood pressure and maternal and neonatal
complications. J Matern Fetal Neonatal Med 2010;23:1456-60.
24 Sibai BM, Lindheimer M, Hauth J, Caritis S, VanDorsten P, Klebanoff M, et al. Risk factors
for preeclampsia, abruptio placentae, and adverse neonatal outcomes among women
with chronic hypertension. N Engl J Med 1998;339:667-71.
25 Allen VM, Joseph KS, Murphy KE, Magee LA, Ohlsson A. The effect of hypertensive
disorders in pregnancy on small for gestational age and stillbirth: a population based
study. BMC Pregnancy Childbirth 2004;4:17.
26 Bateman BT, Bansil P, Hernandez-Diaz S, Mhyre JM, Callaghan WM, Kuklina EV.
Prevalence, trends, and outcomes of chronic hypertension: a nationwide sample of delivery
admissions. Am J Obstet Gynecol 2012;206:134.e1-34.e8.
27 Broekhuijsen K, Langenveld J, Van Den Berg P, Ravelli A, Willem Mol B, Franssen M.
Maternal and neonatal outcomes of pregnancy in women with chronic hypertension. Am
J Obstet Gynecol 2012;1:S344-5.
28 Rasmussen S, Irgens LM. The effects of smoking and hypertensive disorders on fetal
growth. BMC Pregnancy Childbirth 2006;6:16.
29 Roberts CL, Algert CS, Morris JM, Ford JB, Henderson-Smart DJ. Hypertensive disorders
in pregnancy: a population-based study. Med J Aust 2005;182:332-5.
30 Su CY, Lin HC, Cheng HC, Yen AMF, Chen YH, Kao S. Pregnancy outcomes of
anti-hypertensives for women with chronic hypertension: a population-based study. Plos
One 2013;8:e53844.
31 Zetterstrom K, Lindeberg SN, Haglund B, Hanson U. The association of maternal chronic
hypertension with perinatal death in male and female offspring: a record linkage study of
866,188 women. BJOG 2008;115:1436-42.
32 Attolou VNR. Les differents types d’hypertension arterielle chez les femmes enceintes
beninoises admises au CNHU de Cotonou [Types of arterial hypertension in pregnant
women admitted to the National University Hospital (CNHU), Cotonou, Benin] [French].
Cahiers Sante 1998;8:353-6.
33 Curet LB, Olson RW. Evaluation of a program of bed rest in the treatment of chronic
hypertension in pregnancy. Obstet Gynecol 1979;53:336-40.
34 Fleischer A, Schulman H, Farmakides G. Uterine artery Doppler velocimetry in pregnant
women with hypertension. Am J Obstet Gynecol 1986;154:806-13.
35 Gant NF, Jimenez JM, Whalley PJ, Chand S, MacDonald PC. A prospective study of
angiotensin II pressor responsiveness in pregnancies complicated by chronic essential
hypertension. Am J Obstet Gynecol 1977;127:369-75.
36 Hartikainen AL, Aliharmi RH, Rantakallio PT. A cohort study of epidemiological associations
and outcomes of pregnancies with hypertensive disorders. Hypertens Pregnancy
1998;17:31-41.
37 Inigo Riesgo CA, Torres Gomez LG, Vargas Gonzalez A, Angulo Vazquez J, Espinoza
Ortegon MA. [Chronic high blood pressure in 110 pregnant women] [Spanish]. Ginecol
Obstet Mex 2008;76:202-10.
38 Jacquemyn Y, Osmanovic F, Martens G. Preeclampsia and birthweight by gestational
age in singleton pregnancies in Flanders, Belgium: a prospective study. Clin Exp Obstet
Gynecol 2006;33:96-8.
39 Mabie WC, Pernoll ML, Biswas MK. Chronic hypertension in pregnancy. Obstet Gynecol
1986;67:197-205.
40 Onyiriuka AN, Okolo AA. Small-for-gestational age, ponderal index and neonatal
polycythaemia: a study of their association with maternal hypertension among Nigerian
women. Ann Afr Med 2005;4:154-59.
41 Ray JG, Burrows RF, Burrows EA, Vermeulen MJ. MOS HIP: McMaster outcome study
of hypertension in pregnancy. Early Hum Dev 2001;64:129-43.
42 Rey E, Couturier A. The prognosis of pregnancy in women with chronic hypertension. Am
J Obstet Gynecol 1994;171:410-6.
43 Rey E. Preeclampsia and neonatal outcomes in chronic hypertension: comparison between
white and black women. Ethn Dis 1997;7:5-11.
44 Roncaglia N, Crippa I, Locatelli A, Cameroni I, Orsenigo F, Vergani P, et al. Prediction of
superimposed preeclampsia using uterine artery Doppler velocimetry in women with
chronic hypertension. Prenat Diagn 2008;28:710-4.
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 6 of 20
RESEARCH
45 Ruiz Anguas J, Castelazo Morales E, Suarez del Puerto H, Martinez Moreno F, Alvarez
Valenzuela J, Bolanos Ancona RA. [Perinatal results in patients with chronic hypertension
at the National Institute of Perinatology] [Spanish]. Ginecol Obstet Mex 2001;69:143-50.
46 Segel S, Ananthakrishnan B, Merrill J, Parry S, Macones G, Marder S. Mild chronic
hypertension does not confer an increased risk for small for gestational age neonates.
Am J Obstet Gynecol 2001;185:S181.
47 Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in 211 patients with mild chronic
hypertension. Obstet Gynecol 1983;61:571-6.
48 Sibai BM, Anderson GD. Pregnancy outcome of intensive therapy in severe hypertension
in first trimester. Obstet Gynecol 1986;67:517-22.
49 Sun Y, Yang YL, Yang HX. [Maternal and perinatal prognosis of pregnancy with chronic
hypertension and analysis of associated factors] [Chinese]. Zhonghua fu chan ke za zhi
2007;42:434-7.
50 Valsecchi L, Cairone R, Castiglioni MT, Almirante GM, Ferrari A. Serum levels of
alpha-tocopherol in hypertensive pregnancies. Hypertens Pregnancy 1999;18:189-95.
51 Zeeman GG, Alexander JM, McIntire DD, Leveno KJ. The significance of antiphospholipid
antibodies in pregnant women with chronic hypertension. Am J Perinatol 2004;21:275-9.
52 Ales KL, Charlson ME. The prediction of adverse outcomes in antepartum hypertension.
Clin Exp Hypertens B 1989;8:95-112.
53 Bagga R, Aggarwal N, Chopra V, Saha SC, Prasad GRV, Dhaliwal LK. Pregnancy
complicated by severe chronic hypertension: a 10-year analysis from a developing country.
Hypertens Pregnancy 2007;26:139-49.
54 Banhidy F, Acs N, Puho EH, Czeizel AE. The efficacy of antihypertensive treatment in
pregnant women with chronic and gestational hypertension: a population-based study.
Hypertens Res 2010;33:460-6.
55 Comino-Delgado R. ‘Hypertensive states of pregnancy’ in Spain. Clin Exp Hypertens B
1986;5:217-30.
56 Delmis J, Drazancic A, Ivanisevic M, Pfeifer D, Ljubojevic N. [Fetal growth in pregnant
women with chronic hypertension] [Croatian]. Lijec Vjesn 1993;115:329-35.
57 Ferrazzani S, Luciano R, Garofalo S, D’Andrea V, De Carolis S, De Carolis MP, et al.
Neonatal outcome in hypertensive disorders of pregnancy. Early Hum Dev 2011;87:445-9.
58 Fields SJ, Vainder M, Livshits G, Merlob P, Sirotta L. Obesity and the risk of toxaemia of
pregnancy. Ann Hum Biol 1996;23:353-62.
59 Frusca T, Soregaroli M, Zanelli S, Danti L, Guandalini F, Valcamonico A. Role of uterine
artery Doppler investigation in pregnant women with chronic hypertension. Eur J Obstet
Gynecol Reprod Biol 1998;79:47-50.
60 Gilbert WM, Young AL, Danielsen B. Pregnancy outcomes in women with chronic
hypertension: a population-based study. J Reprod Med 2007;52:1046-51.
61 Jain L. Effect of pregnancy-induced and chronic hypertension on pregnancy outcome. J
Perinatol 1997;17:425-7.
62 Lecarpentier E, Tsatsaris V, Goffinet F, Cabrol D, Sibai B, Haddad B. Risk factors of
superimposed preeclampsia in women with essential chronic hypertension treated before
pregnancy. Plos One 2013;8:e62140.
63 Lydakis C, Beevers DG, Beevers M, Lip GY. Obstetric and neonatal outcome following
chronic hypertension in pregnancy among different ethnic groups. QJM 1998;91:837-44.
64 Machado MH, Clode N, Graca LM, Cardoso CG. Hypertension associated with pregnancy.
Hipertensao associada a gravidez. Estudo epidemiologico de 311 casos consecutivos
[Epidemiologic study of 311 consecutive cases] [Portuguese]. Acta Medica Portuguesa
1996;9:7-14.
65 Ono Y, Takagi K, Seki H, Takai Y, Samejima K, Matsunaga S, et al. Neonatal outcome
in infants of chronically hypertensive mothers. J Obstet Gynaecol Res 2013;39:1142-6.
66 Parry S, Macones GA, Roth NW, Desperito TJ, Marzullo A, Morgan MA. Antiphospholipid
antibodies in chronic hypertension: the value of screening during pregnancy. Am J Perinatol
1998;15:527-31.
67 Pietrantoni M, O’Brien WF. The current impact of the hypertensive disorders of pregnancy.
Clin Exp Hypertens 1994;16:479-92.
68 Sass N, Moron AF, el-Kadre D, Camano L, de Almeida PA. Contribuicao ao estudo da
gestacao em portadoras de hipertensao arterial cronica [Study of pregnancy with chronic
hypertension] [Portuguese]. Revista Paulista de Medicina 1990;108:261-6.
69 Tuuli MG, Rampersad R, Stamilio D, Macones G, Odibo AO. Perinatal outcomes in women
with preeclampsia and superimposed preeclampsia: do they differ? Am J Obstet Gynecol
2011;204:508.e1-7.
70 Vanek M, Sheiner E, Levy A, Mazor M. Chronic hypertension and the risk for adverse
pregnancy outcome after superimposed pre-eclampsia. Int J Gynaecol Obstet
2004;86:7-11.
71 Velentgas P, Benga-De E, Williams MA. Chronic hypertension, pregnancy-induced
hypertension, and low birthweight. Epidemiology 1994;5:345-8.
72 Vigil-De Gracia P, Lasso M, Montufar-Rueda C. Perinatal outcome in women with severe
chronic hypertension during the second half of pregnancy. Int J Gynaecol Obstet
2004;85:139-44.
73 Wilson K, Roberts S, McIntire D, Alexander JM. Indication for delivery in pregnant women
with chronic hypertension. Am J Obstet Gynecol 2012;1:S343.
74 Zeeman G, Alexander J, McIntire D, Leveno K. Pregnancy outcomes in chronic
hypertension compared with the general obstetric population. Am J Obstet Gynecol
2003;189:S89.
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014)
75 Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MVC, Martins-Costa S, et al. The
impact of prior preeclampsia on the risk of superimposed preeclampsia and other adverse
pregnancy outcomes in patients with chronic hypertension. Am J Obstet Gynecol
2011;204:345.e1-6.
76 Giannubilo SR, Dell’Uomo B, Tranquilli AL. Perinatal outcomes, blood pressure patterns
and risk assessment of superimposed preeclampsia in mild chronic hypertensive
pregnancy. Eur J Obstet Gynecol Reprod Biol 2006;126:63-7.
77 McCowan LM, Buist RG, North RA, Gamble G. Perinatal morbidity in chronic hypertension.
Br J Obstet Gynaecol 1996;103:123-9.
78 Ananth CV, Peltier MR, Kinzler WL, Smulian JC, Vintzileos AM. Chronic hypertension
and risk of placental abruption: is the association modified by ischemic placental disease?
Am J Obstet Gynecol 2007;197:273.e1-7.
79 Sibai B, Koch M, Freire S, Pinto ES, Rudge MV, Martins-Costa S, et al. Are adverse
perinatal outcomes (APOs) in chronic hypertension (CHTN) mostly related to superimposed
preeclampsia (PE)? Am J Obstet Gynecol 2012;206:S57.
80 Chappell L, Poulton L, Halligan A, Shennan AH. Lack of consistency in research papers
over the definition of pre-eclampsia. Br J Obstet Gynaecol 1999;106:983-5.
81 Cnossen JS, Vollebregt KC, de Vrieze N, ter Riet G, Mol BW, Franx A, et al. Accuracy of
mean arterial pressure and blood pressure measurements in predicting pre-eclampsia:
systematic review and meta-analysis. BMJ 2008;336:1117-20.
82 Duvekot JJ, Cheriex EC, Pieters FA, Menheere PP, Peeters LH. Early pregnancy changes
in hemodynamics and volume homeostasis are consecutive adjustments triggered by a
primary fall in systemic vascular tone. Am J Obstet Gynecol 1993;169:1382-92.
83 Brown MA, Lindheimer MD, de Swiet M, Van Assche A, Moutquin JM. The classification
and diagnosis of the hypertensive disorders of pregnancy: statement from the International
Society for the Study of Hypertension in Pregnancy (ISSHP). Hypertens Pregnancy
2001;20:IX-XIV.
84 Centre for Maternal and Child Enquiries (CMACE). Saving mothers’ lives: reviewing
maternal deaths to make motherhood safer: 2006-08. The eighth report on Confidential
Enquiries into Maternal Deaths in the United Kingdom. BJOG 2011;118(suppl 1):1-203.
85 National Institute for Health and Clinical Excellence. Hypertension in pregnancy: the
management of hypertensive disorders during pregnancy. NICE, 2010 (available at http:
//publications.nice.org.uk/hypertension-in-pregnancy-cg107). (Clinical Guideline 107.)
No commercial reuse: See rights and reprints http://www.bmj.com/permissions
Page 7 of 20
RESEARCH
86 American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 125:
Chronic hypertension in pregnancy. Obstet Gynecol 2012;119:396-407.
87 Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive drug therapy for
mild to moderate hypertension during pregnancy. Cochrane Database Syst Rev
2007;(1):CD002252.
88 Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal exposure to angiotensin
converting enzyme inhibitors in the first trimester and risk of malformations in offspring:
a retrospective cohort study. BMJ 2011;343:d5931.
89 Von Dadelszen P, Ornstein MP, Bull SB, Logan AG, Koren G, Magee LA. Fall in mean
arterial pressure and fetal growth restriction in pregnancy hypertension: a meta-analysis.
Lancet 2000;355:87-92.
90 The CHIPS trial: Control of Hypertension In Pregnancy Study. International Standard
Randomised Controlled Trial Register . www.controlled-trials.com/ISRCTN71416914/.
91 Su CY, Lin HC, Cheng HC, Yen AM, Chen YH, Kao S. Pregnancy outcomes of
anti-hypertensives for women with chronic hypertension: a population-based study. PloS
One 2013;8:e53844.
92 Thangaratinam S, Rogozinska E, Jolly K, Glinkowski S, Roseboom T, Tomlinson JW, et
al. Effects of interventions in pregnancy on maternal weight and obstetric outcomes:
meta-analysis of randomised evidence. BMJ 2012;344:e2088.
93 Palmsten K, Buka SL, Michels KB. Maternal pregnancy-related hypertension and risk for
hypertension in offspring later in life. Obstet Gynecol 2010;116:858-64.
Accepted: 12 March 2014
Cite this as: BMJ 2014;348:g2301
This is an Open Access article distributed in accordance with the Creative Commons
Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute,
remix, adapt, build upon this work non-commercially, and license their derivative works
on different terms, provided the original work is properly cited and the use is
non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/.
Subscribe: http://www.bmj.com/subscribe
BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 8 of 20

RESEARCH

Tables

Table 1| Overview of randomised controlled trials of pregnancy outcomes in women with chronic hypertension included in meta-analysis

Multiple Secondary causes of Congenital Definition of

Author, year No of No of gestations chronic hypertension abnormalities chronic Newcastle-Ottowa
published Study years Country women births included excluded excluded hypertension* grade
August et al, 2003 USA 110 110 No Creatinine >1.2 mg/dL No 3 7
200422 excluded
Chappell et al, 2003-05 UK and 822 822 No No No 2 7
200815 Netherlands
Neri et al, 201023 2006-08 Italy 40 40 No Known cardiac or renal Yes 1 6
disease excluded
Sibai et al, ?-1998 USA 763 763 No Type 1 diabetes No 4 7
199824 excluded
Weitz et al, ?-1986 USA 25 25 No No evidence of No 2 6
198716 proteinuria (24 hour
urine protein <100 mg)

*1=systolic blood pressure >140 or diastolic blood pressure >90 mm Hg and/or history of hypertension; 2=diastolic blood pressure >90 mm Hg and/or history of
hypertension; 3=history of hypertension before pregnancy or presence of hypertension before 20 weeks with no blood pressure definition; 4=blood pressure
>140/90 mm Hg; 5=history of hypertension only; 6=antihypertensive drug treatment before 20 weeks; 7=other.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 9 of 20

RESEARCH

Table 2| Overview of population studies of pregnancy outcomes in women with chronic hypertension included in meta-analysis

Secondary causes
Multiple of chronic Congenital Definition of
Author, year No of No of gestations hypertension abnormalities chronic Newcastle-Ottowa
published Study years Country women births included excluded excluded hypertension* grade
Allen et al, 200425 1988-2000 Canada 1242 1258 Yes No Yes 3 7
Bateman et al, 1995-2008 USA 731 694 (649 750 078 Yes Primary and No 5 7
201226 899 primary, secondary defined
81 795
secondary)
Broekhuijsen et 2002-07 Netherlands 1609 1609 No “Relevant Yes 2 6
al, 201227 comorbidity
excluded”
Rasmussen et al, 1999-2002 Norway 1116 1116 No Women with renal No 4 7
200628 disease, cardiac
disease, diabetes
mellitus excluded
Roberts et al, 2000-02 Australia 2162 2162 No No No 2 7
200529
Su et al, 201330 2005 Taiwan 2727 2727 No No No 2 7
Zetterstrom et al, 1992-2004 Sweden 4749 4749 No No No 1 7
200831

*1=systolic blood pressure >140 or diastolic blood pressure >90 mm Hg and/or history of hypertension; 2=diastolic blood pressure >90 mm Hg and/or history of
hypertension; 3=history of hypertension before pregnancy or presence of hypertension before 20 weeks with no blood pressure definition; 4=blood pressure
>140/90 mm Hg; 5=history of hypertension only; 6=antihypertensive drug treatment before 20 weeks; 7=other.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 10 of 20

RESEARCH

Table 3| Overview of prospective studies of pregnancy outcomes in women with chronic hypertension included in meta-analysis

Secondary causes
Multiple of chronic Congenital Definition of
Author, year No of No of gestations hypertension abnormalities chronic Newcastle-Ottowa
published Study years Country women births included excluded excluded hypertension* grade
Attolou et al, 199832 1995-96 Benin 64 64 No Cardiac or renal No 2 7
disease excluded
Curet et al, 197933 1973-79 USA 66 72 Yes “No diabetes, cardiac No 1 6
or renal disease”
Fleischer et al, 1982-84 USA 55 55 No No No 1 6
198634
Gant et al, 197735 ?-1977 USA 63 63 No “Essential No 3 6
hypertension only”
Hartikainen et al, 1985-86 Finland 396 396 No No No 1 7
199836
Inigo Riesgo et al, 2001-07 Mexico 110 110 No “Mild chronic No 1 6
200837 hypertension without
other disease”
Jacquemyn et al, 2001-02 Belgium 2393 2393 No No No 1 7
200638
Mabie et al, 198639 1980-84 USA 156 169 Yes No No 2 6
Onyiriuka and Okolo, 1992-94 Nigeria 20 20 No “Free of major No 2 6
200540 diseases such as
diabetes mellitus,
sickle cell anaemia,
renal failure and heart
disease”
Ray, 200141 1986-95 Canada 459 459 No No No 1 7
Rey and Couturier, 1987-91 Canada 298 Unknown Unknown No No 1 7
199442
Rey, 199743 1987-91 USA 208 208 Yes Renal disease and No 1 7
pre-pregnancy
diabetes excluded
Roncaglia et al, 2000-06 Italy 182 182 No Excluded proteinuria Yes 1 7
200844 at first visit
Ruiz et al, 200145 1996-97 Mexico 66 66 No No No 5 7
Segel et al, 200146 1995-2001 USA 131 131 No No No 1 6
Sibai et al, 1983 47
1980-82 USA 211 215 No No No 6 6
Sibai et al, 198648 1978-84 USA 44 44 No No No 6 6
Sun et al, 200749 2001-05 China 121 121 No No No 2 7
Valsecchi et al, 1993-96 Italy 26 26 No No No 3 6
199950
Zeeman et al, 200451 1999-2002 USA 87 87 No No No 2 6

*1=systolic blood pressure >140 or diastolic blood pressure >90 mm Hg and/or history of hypertension; 2=diastolic blood pressure >90 mm Hg and/or history of
hypertension; 3=history of hypertension before pregnancy or presence of hypertension before 20 weeks with no blood pressure definition; 4=blood pressure
>140/90 mm Hg; 5=history of hypertension only; 6=antihypertensive drug treatment before 20 weeks; 7=other.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 11 of 20

RESEARCH

Table 4| Overview of retrospective studies of pregnancy outcomes in women with chronic hypertension included in meta-analysis

Secondary causes
Multiple of chronic Congenital Definition of
Author, year No of No of gestations hypertension abnormalities chronic Newcastle-Ottowa
published Study years Country women births included excluded excluded hypertension* grade
Ales et al, 198952 1981 USA 30 31 Yes No No 2 6
Bagga et al, 200753 1995-2004 India 72 72 No No No 7 6
Banhidy et al, 201054 1980-96 Hungary 1579 1627 Yes “Secondary Yes 2 6
hypertension
excluded”
Comino-Delado et al, 1984 Spain 447 447 No No No 1 5
198655
Delmis et al, 199356 1987-90 Croatia 210 210 Yes No No 1 7
Ferrazzani et al, 1986-95 Italy 210 210 No No No 3 6
201157
Fields et al, 199658 1990-92 Israel 52 52 No No No 1 6
Frusca et al, 199859 1993-95 Italy 78 78 No No proteinuria at Yes 7 7
entry or secondary
hypertension
Gilbert et al, 200760 1991-2001 USA 29 842 29 917 Yes No No 2 7
Jain, 199761 1982-87 USA 2048 2048 No No No 3 6
Lecarpentier, 201362 2004-07 France 211 211 No Secondary Yes 6 6
hypertension
excluded
Lydakis et al, 199863 1980-97 UK 152 213 No Diabetes, renal No 1 5
disease, secondary
forms of
hypertension
excluded
Machado et al, 1988-92 Portugal 97 98 Yes No No 1 6
199664
Ono et al, 201365 2006-09 Japan 120 120 No Secondary No 1 7
hypertension
excluded
Parry et al, 199866 1992-95 USA 70 70 No Secondary Yes 1 7
hypertension
excluded
Pietrantoni et al, 1987 USA 109 109 No No No 1 6
199467
Sass et al, 199068 1985-86 Brazil 189 189 No No No 1 6
Tuuli et al, 2011 69
1990-2008 USA 1032 1032 No No Yes 2 7
Vanek et al, 200470 1988-99 Israel 1807 1807 No No No 2 7
Velentgas et al, ?-1994 USA 4014 4014 No Not complicated by No 3 7
199471 cardiac disease,
renal disease,
diabetes mellitus
Vigi-De-Gracia et al, 1996-2001 Panama 154 157 Yes No No 7 6
200472
Wilson et al, 201273 2008-10 USA 165 165 No No No 5 6
Zeeman et al, 200374 ?-2003 USA 117 117 No No No 2 6

*1=systolic blood pressure >140 or diastolic blood pressure >90 mm Hg and/or history of hypertension; 2=diastolic blood pressure >90 mm Hg and/or history of
hypertension; 3=history of hypertension before pregnancy or presence of hypertension before 20 weeks with no blood pressure definition; 4=blood pressure
>140/90 mm Hg; 5=history of hypertension only; 6=antihypertensive drug treatment before 20 weeks; 7=other.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 12 of 20

RESEARCH

Table 5| Estimated incidence and prediction intervals of adverse pregnancy outcomes for women with chronic hypertension

Outcome No of studies Estimated incidence (%) (95% CI) Prediction intervals (95%) Heterogeneity τ2
Superimposed pre-eclampsia 38 25.9 (21.0 to 31.5) 5.5 to 67.2 0.766
Caesarean section 27 41.4 (35.5 to 47.7) 15.5 to 73.2 0.413
Pre-term delivery (<37 weeks) 30 28.1 (22.6 to 34.4) 6.8 to 67.6 0.286
Birth weight <2500 g 14 16.9 (13.1 to 21.5) 5.7 to 40.6 0.286
Neonatal intensive care 16 20.5 (15.7 to 26.4) 5.9 to 51.3 0.403
Perinatal death 27 4.0 (2.9 to 5.4) 0.9 to 16.4 0.544

95% prediction intervals show uncertainty of range of possible incidence percentages for new study population, whereas 95% confidence intervals show uncertainty
about estimate of average percentage incidence across study populations.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 13 of 20

RESEARCH

Table 6| Estimated incidence and prediction intervals of adverse pregnancy outcomes for women with chronic hypertension: studies
conducted in United States compared with US general population data
21

US general
Estimated incidence (%) Prediction interval population
Outcome No of studies (95% CI) (95%) incidence (%) Risk ratio (95% CI) Heterogeneity τ2
Superimposed 38 29.2 (21.6 to 38.2) 6.6 to 70.3 3.8 7.7 (5.7 to 10.1) 0.623
pre-eclampsia
Caesarean section 27 42.4 (35.0 to 50.1) 18.4 to 70.7 32.9 1.3 (1.1 to 1.5) 0.258
Pre-term delivery (<37 30 33.0 (23.7 to 44.0) 7.8 to 74.1 12.2 2.7 (1.9 to 3.6) 0.526
weeks)
Birth weight <2500 g 14 22.2 (15.4 to 30.9) 5.1 to 60.5 8.2 2.7 (1.9 to 3.8) 0.225
Neonatal intensive care 16 19.3 (13.4 to 27.0) 5.0 to 51.9 6.1 3.2 (2.2 to 4.4) 0.246
Perinatal death 27 4.6 (3.0 to 7.1) 1.0 to 18.9 1.1 4.2 (2.7 to 6.5) 0.429

95% prediction intervals show uncertainty of range of possible incidence percentages for new study population, whereas 95% confidence intervals show uncertainty
about estimate of average percentage incidence across study populations.

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 14 of 20

RESEARCH

Figures

Fig 1 Flow chart of study selection process

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 15 of 20

RESEARCH

Fig 2 Forest plot of studies of superimposed pre-eclampsia in women with chronic hypertension stratified according to study
design. MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 16 of 20

RESEARCH

Fig 3 Forest plot of studies of caesarean section in women with chronic hypertension stratified according to study design.
MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 17 of 20

RESEARCH

Fig 4 Forest plot of studies of preterm delivery before 37 weeks’ gestation in women with chronic hypertension stratified
according to study design. MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 18 of 20

RESEARCH

Fig 5 Forest plot of studies of birth weight <2500 g in women with chronic hypertension stratified according to study design.
MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 19 of 20

RESEARCH

Fig 6 Forest plot of studies of neonatal unit admission in women with chronic hypertension stratified according to study
design. MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe

BMJ 2014;348:g2301 doi: 10.1136/bmj.g2301 (Published 15 April 2014) Page 20 of 20

RESEARCH

Fig 7 Forest plot of studies of perinatal death in women with chronic hypertension stratified according to study design.
MELR=mixed effects logistic regression

No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe